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Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identiﬁcation of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inﬂammation in individuals with serious mental illness.”

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inﬂammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inﬂammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inﬂammation may be associated not only with a proclivity for a psychiatric disorder, but speciﬁcally with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inﬂammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inﬂammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inﬂammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically signiﬁcant diﬀerence between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was signiﬁcantly higher…We also found that the level of IgG antibodies to gliadin was signiﬁcantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was signiﬁcantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a signiﬁcantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inﬂammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inﬂammation can be modulated by dietaryinterventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identiﬁcation of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

ALS (amyotrophic lateral sclerosis) is a devastating, lethal autoimmune disease characterized by progressive inflammatory degeneration of motor neurons in the brain cortex, brainstem and ventral (front half) of the spinal cord. Non-celiac gluten sensitivity often entails a neurological target for autoimmune attack in the absence of abdominal symptoms. In a study just published in JAMA Neurology, investigators report an association between some cases of ALS and gluten sensitivity. They state:

“Celiac disease is an autoimmune disorder triggered by gluten in genetically predisposed individuals. Gluten sensitivity can cause neurologic manifestations, such as ataxia or neuropathy, with or without gastrointestinal symptoms. Many patients with gluten ataxia produce antibodies toward the newly identified neuronal transglutaminase 6 (TG6). Two case reports described patients initially diagnosed with amyotrophic lateral sclerosis (ALS) and ultimately with celiac disease who improved with a strict gluten-free diet.“

To determine whether a gluten-related disorder mimicking ALS might occur in some patients they set out to look for celiac disease–related antibodies and HLA antigen alleles along with TG6 antibodies in patients with ALS compared to healthy individuals. They measured serum levels of total IgA antibodies, IgA antibodies to transglutaminase 2 (TG2) and endomysium, IgA and IgG antibodies to deamidated gliadine peptide, and TG6; and performed HLA antigen genotyping in 150 patients with ALS and 115 healthy volunteers. A striking picture emerged:

“All patients and control group participants were seronegative to IgA antibodies to TG2, endomysium, and deamidated gliadine peptide. Twenty-three patients (15.3%) were seropositive to TG6 IgA antibodies as opposed to only 5 controls (4.3%). The patients seropositive for TG6 showed a classic picture of ALS, similar to that of seronegative patients.”

“The data from this study indicate that, in certain cases, an ALS syndrome might be associated with autoimmunity and gluten sensitivity. Although the data are preliminary and need replication, gluten sensitivity is potentially treatable; therefore, this diagnostic challenge should not be overlooked.“

Gluten intolerance can occur at any age due to a number of causes that contribute to loss of immune tolerance. The authors of a paper published recently in the journal Gastroenterology and Hepatology from Bed to Bench remind how a bout of viral or bacterial gastroenteritis can be the trigger. They state:

“The spectrum of irritable bowel syndrome (IBS) is narrowing and many conditions previously known/attributed to IBS seem to be related to unrecognised primary or acquired intolerances to nutrient components. Infection might act as triggering factor for inflammatory conditions in susceptible individuals…Inflammation of absorptive surface leading to various enzymatic defects, changing the microbiota and increasing intestinal permeability may result in symptoms previously known as post gastroenteritis IBS. It is time to recognise the possible pathophysiology of acquired gluten intolerance that has been miss-treated under the mask of IBS.”

By way of authors report on a case of IBS occurring only after gastroenteritis that resolved on a gluten-free and lactose-free diet.

Clinicians doing case management of autoimmunity are well aware that infection can trigger latent loss of immune tolerance. One mechanism is through compromise of the barrier systems (gut, respiratory, blood-brain).

“Viral or bacterial gastroenteritis can cause structural changes to the small bowel mucosa, including locally reduced digestive enzymes activities secondary to the local inflammatory reaction. Peptidase deficiency resulting from infected small bowel can cause accumulation of partially digested gluten peptides and damage the intestinal mucosal cell. We speculate that damages and deficiencies might cause transitory or permanent intolerances to gluten and other nutrients…involvement of the small bowel and colon may cause IBS-like symptoms, whereas involvement of the stomach and duodenum may cause functional dyspepsia.”

Gluten intolerance after gastroenteritis may be common

An earlier post reports on loss of immune tolerance to the normal commensal gut microbiota after food borne illness. Practitioners should be alert to complaints persisting after resolution of a GI infection.

“Transient or permanent post gastroenteritis gluten intolerance might be a common unrecognised clinical condition. Like secondary lactose intolerance, post gastroenteritis gluten intolerance could explain the prolonged symptoms that develop in a group of patients who have suffered from infective gastroenteritis. Patients may present with diarrhoea, bloating, pain, vomiting and dyspepsia.”

Non-celiac gluten sensitivity

Gluten intolerance should be considered as a possibility under the same circumstances that would suggest lactose intolerance.

“Non-coeliac gluten sensitivity is an entity separate from coeliac disease with a much higher prevalence. The autoantibodies like anti-EMA and/or anti-tTG tests are negative although antigliadin antibodies may be present…We suggest there may be an important role for the reduction of gluten in the diet as a treatment for these patients, in a manner analogous to the reduction in lactose intake frequently advised by dieticians for symptoms attributed to transient post infectious lactose intolerance.”

The authors conclude:

“We suspect that patients who develop lactose and gluten intolerances after an episode of gastroenteritis are labelled as having IBS and can be left untreated for years or given only symptomatic treatment for pain, diarrhoea and constipation rather than advised to reduce their dietary intake of lactose and gluten. By moving toward clear diagnosis and targeted treatment of diseases that are involved in the formation of symptoms, we proportionally are approaching the end of the era of non-specific and unhelpful diagnosis like IBS and post gastroenteritis IBS. Clinician and dietician considering the possibility of a post infectious gastroenteritis irritable bowel syndrome being, in part, due to gluten intolerance may encourage colleagues to consider introducing a trial of a lactose and gluten free diet in suitable candidates after exclusion of celiac disease.”

Gluten free labeling is, sadly, not a guarantee of safety for those with celiac disease or non-celiac gluten sensitivity as demonstrated in a study recently published in the Journal of Food Protection. The authors state:

“Gluten is the main storage protein in grains and consists of gliadin and glutenin occurring in the same ratio. Persons suffering from intolerances, including celiac disease, must avoid foods containing gluten or products containing wheat, barley, and rye… This study was designed to determine the concentrations of gluten in foods labeled “gluten free” available in the United States.”

Gluten found in diverse products

Many sources of gluten are far from obvious and it may not occur to question whether a product is gluten free.

“Gluten is found not only in all products made with wheat, rye, and barley but also as an ingredient in foods including meat, sausages, soups, and ready-to-eat meals. Due to its physicochemical characteristics, gluten is used in food products to modify both texture, e.g., as a thickener to improve texture and water or fat retention, and form, e.g., to increase the extensibility. Gluten can also be used as an animal protein substitute in meat products to reduce manufacturing costs. Furthermore, gluten and wheat starch are found in some drugs as a filler.”

Standards for ‘Gluten Free’ labeling

There is a significant difference between gluten free and ‘‘foods specially processed to reduce gluten content’’ or ‘‘very low gluten’’.

“To be labeled ‘‘gluten free,’’ products must contain less than 20 mg/kg gluten, i.e., equivalent to 10 mg/kg gliadin, while foods labeled as ‘‘foods specially processed to reduce gluten content’’ or ‘‘very low gluten’’ must comply with levels between 20 and 100 mg/kg. In October 2013, the U.S. Food and Drug Administration (FDA) issued a final rule to define the term ‘‘gluten free’’ for voluntary use in the labeling of foods. According to the final rule, gluten free means that the food bearing the claim does not contain (i) an ingredient that is a gluten-containing grain (e.g., spelt wheat), (ii) an ingredient that is derived from a gluten-containing grain and has not been processed to remove gluten (e.g., wheat flour), or (iii) an ingredient that is derived from a gluten-containing grain and has been processed to remove gluten (e.g., wheat starch) if the use of that ingredient results in the presence of 20 mg/kg or more gluten in the food, or it means that the food (iv) inherently does not contain gluten, and food with any unavoidable presence of gluten that is below 20 mg/kg gluten can be labeled as gluten free.”

Cross-contamination

Cross-contamination of products inherently gluten free can occur in production, transportation and storage.

“Cross-contamination of inherently gluten-free foods can occur at all stages of the food chain, including when they are grown, harvested, and/or processed. Comingling of grain in the field can occur because of crop rotation with wheat, barley, or rye if they are grown next to or in rotation with these grains. It is possible that seeds of the gluten-containing grains will linger in the soil and, as a result, some of the gluten-containing grain may be collected during the same harvest with the inherently gluten-free grain. Sharing of storage facilities where relevant, such as in grain elevators, can result in co-mingling of grains. Further, using the same transportation vehicles for moving the grains to the processing site and sharing of processing facilities and equipment within those facilities can also result in cross-contamination. The presence of wheat in oats is a good example of on-farm cross-contamination…If cross-contamination occurs at any stage in the food chain, undeclared glutens can end up in the processed food products…A few small studies have shown that contamination may occur in gluten-free foods or inherently gluten-free grains and their milled fractions, such as oats, millet flour, and sorghum flour. In addition, gluten has been detected in rice-, corn-, oat-, and buckwheat-based foods with or without the gluten-free label. Hence, the aim of the present study was to analyze foods in the U.S. market labeled gluten free for gluten contamination.”

So the authors randomly collected 78 commercially available samples labeled gluten free were from different local markets in Moscow, Idaho and analyzed them for gliadin content by competitive enzyme-linked immunosorbent assay. Their data engenders concern and vigilance for anyone who truly needs to avoid gluten:

Breakfast cereals were the most frequently contaminated

“Based on the gluten levels of samples, 48 of the 78 (61.5%) products contained gluten below the limit of quantification (less than 10 mg/kg gluten). Fourteen of the 78 (17.9%) products contained a detectable amount of gluten ranging from 10.9 to 18.7 mg/kg. Sixteen (20.5%) of the 78 would not be considered gluten free under the proposed FDA rules for gluten-free labeling. Among other parameters, foods labeled gluten free must contain <20 ppm gluten to be labeled gluten free. The gluten contamination frequency was highest in breakfast cereal (62.5%), followed by bread (37.5%), pasta (23.1%), snack food (13.3%), and baking mix (11.1%).”

Rice and corn products are attractive to those avoiding gluten but are not free of treachery:

“Being the most popular ingredients in gluten-free products, rice and corn might be considered to be safer cereal-based foods for CD patients…of the 16 gluten-contaminated samples, the most contaminated gluten-free food samples were made with rice, corn, or mixed grains, including seven rice-based foods, three corn-based foods, and six mixed-grain-based foods. Moreover, all of 6 mixed-grain-based samples included rice flour. According to our data, the most contaminated samples labeled gluten free were made from rice or corn and the levels of contamination were less than 50 mg/kg gluten.”

Gluten free mislabeling is a world-wide problem

The concern is similar for Europeans and Canadians:

“A few previous studies have examined gluten in gluten- free foods and reported cross-contamination of 14 to 22% in inherently gluten-free foods and 46% in products based on gluten-free wheat starch produced by a deglutination process. According to Valde ́s et al., a study of more than 3,000 gluten-free foods in Europe showed that one third had gluten levels higher than 20 mg/kg, which is above the gluten-free threshold. Another study reported that 5% of 1,583 different products labeled as gluten free contained gluten. In a study of Canadian cereal foods, about 10% of the 77 gluten-free foods were contaminated with gluten.”

Bottom line on gluten free labeling

More rigorous standards of compliance are necessary to ensure the dependability of products labeled or presumed to be gluten free. A product such as rice or corn is being intrinsically gluten free is not sufficient to confirm that it is.

“Products made from inherently gluten-free crops that are labeled gluten free but are not tested to be gluten free may be deemed misbranded if the label implies that all inherently gluten-free crops are free of gluten, since these inherently gluten-free grains, such as rice, corn, and buckwheat, can be contaminated with gluten.”

The authors conclude by recommending the measurement of gluten in all grain based products:

“Under the proposed FDA rule for labeling of foods as gluten free, manufacturers who voluntarily choose to label their single-ingredient grain products as gluten free will have to imply to consumers that since all inherently gluten-free grains, such as rice, corn, millet, buckwheat, and sorghum, are gluten free by nature, their products using these grains are gluten free; this does not guarantee, though, that there will be no gluten contamination. …Statements such as ‘‘all millet is gluten free’’ can be misleading and potentially harmful to the consumer with CD who requires a strict gluten-free diet. Therefore, the determination of gluten in all grain-based products, including those made with inherently gluten-free grains or ingredients, is recommended. This study shows that there is no guarantee that products labeled gluten free are in fact gluten free, which could be harmful for patients with CD.”

What should practitioners and patients do?

Avoiding gluten is necessary in cases of celiac disease or non-celiac gluten sensitivity but is not recommended in the absence of objective evidence of intolerance. The clinical manifestations of both can be widely diverse and a high degree of suspicion is warranted, not only with chronic unexplained gastrointestinal complaints but also a wide range of disorders with an autoimmune component. A comprehensiveWheat/Gluten Proteome Reactivity & Autoimmunity™ panelis necessary to avoid false negatives.

When indicated diligence in remaining gluten free is warranted, but it is unrealistic to expect that inadvertent exposure will never occur. Overall case management mandates a treatment plan that includes support for immune tolerance and regulation of inflammation. Additionally, supplementation during times of heightened risk (such as eating meals outside the home) with enzymes that break down gliadin and wholesome natural anti-inflammatory agents can significantly ameliorate the effect of inadvertent exposure.

Neuropsychiatric illness can result from neuroinflammation due to a variety of causes. Recent studies offer more evidence that depression and other neuropsychiatric disorders can be a manifestation of non-celiac gluten sensitivity. A paper published in Gastroenterology Research and Practice explores the pathophysiologic mechanisms by which gluten sensitivity can present as a variety of neuropsychiatric conditions in the absence of celiac disease. The authors note:

“…emerging scientific literature has noted a link between gluten ingestion and symptomatology from nearly every organ system, often in the absence of classic histological findings of CD on intestinal biopsy…It has been hypothesized for quite some time that gluten sensitivity may also impair central nervous system functioning. In 1996, Hadjivassiliou et al. found a significant difference in the prevalence of patients with positive antigliadin antibodies amongst those with neurological symptoms of unknown cause (57%) compared to a control group of healthy patients (12%). Amid the 57% who did have positive antibody titres, the majority did not demonstrate histological evidence diagnostic of celiac disease. In a 2010 article published in Lancet Neurology, Hadjivassiliou and colleagues published additional support for the link between gluten sensitivity and neurological manifestations, including ataxia, neuropathy, encephalopathy, epilepsy, myopathy, and myelopathy. Similar results continue to be reported in the medical literature and give credence to the association between gluten sensitivity and neurological symptoms in the absence of celiac disease.”

They present an illustrative case of a 23-year-old woman with a longstanding history of auditory and visual hallucinations that completely resolved by avoiding gluten, and would recur when provoked by a gluten exposure. The authors state:

“There have been multiple reports linking celiac disease and/or gluten sensitivity with mental health manifestations including isolated psychosis and full blown schizophrenia. As in our case history, these cases report complete symptom resolution with removal of gluten. There is also evidence of frequent gluten sensitivity (but not celiac disease) in schizophrenic patients. Furthermore, similar reports are published dealing with various other neurological manifestations in response to gluten exposure including “idiopathic” ataxia and neuropathies, epilepsy, mood swings, and autism. In addition to neuropsychiatric phenomena, there are reports of other organ system involvement including reversible cardiomyopathy, resolved primary infertility, uveitis, and osteoporosis in relation to the gluten exposure in celiac disease.”

“This mechanism of disease has recently been described and discussed in the scientific literature, whereby accumulated toxic insults often resulting from adverse chemical exposures lead to hypersensitivity and impaired tolerance of the immune system (known as toxicant induced loss of tolerance or “TILT”). With growing attention in the medical literature to the escalating problem of toxicant exposure and bioaccumulation within contemporary society, this mechanism of illness has become compelling indeed. Notable groups such as the World Health Organization and the Centers for Disease Control have recently drawn attention to the reality of ubiquitous toxicant exposures and the chemical erosion of human health associated with toxicant accrual within the human body.”

As for TILT in gluten-induced neuropsychiatric disease:

“After the bioaccumulation of a toxicant burden and the consequent immune dysregulation, seemingly insignificant environmental triggers can lead to the release of proinflammatory cytokines, antibodies, chemokines, and interleukins and produce a variety of symptoms, including neuropsychiatric issues, in the affected patient. Gluten is one such common trigger, and is hypothesized to be the culprit in the above case report. With the ability of SRI to induce multisystem manifestations and with its increasing and widespread prevalence, this mechanism of disease is the preferred explanation of the authors for gluten-induced neuropsychiatric disease…This mechanism also explains the apparently inexplicable onset of gluten sensitivity in patients who were previously well and fully tolerant of gluten and accounts for the reversal of gluten sensitivity in some patients who are successful in eliminating their toxicant burden.”

Commenting in conclusion on their case presentation:

“The individual in the presented case demonstrates a clear sensitivity to gluten with remission of longstanding hallucinations with gluten elimination and relapsing symptoms upon reintroduction of dietary gluten. The scientific literature contains numerous case reports where unexplained symptoms are significantly improved and, at times, completely resolved when similar dietary changes are made. Therefore, when clinicians are faced with physical symptoms that have not been otherwise explained, celiac testing may be warranted. If this is found to be negative, the possibility of NCGS and SRI ought to be considered. Although NCGS cannot be definitively diagnosed at this time based on laboratory investigations, a trial of gluten elimination should be incorporated as part of the clinical assessment and potential management.”

Non-celiac gluten sensitivity may be a part of a constellation of symptoms resulting from a toxicant induced loss of tolerance (TILT).

Depression In Non-Celiac Gluten Sensitivity

A recent clinical trial investigating depression in non-celiac gluten sensitivity was recently published in Alimentary Pharmacology and Therapeutics that demonstrated depression in the absence of gastrointestinal symptoms. The authors state:

“Current evidence suggests that many patients with self-reported non-coeliac gluten sensitivity (NCGS) retain gastrointestinal symptoms on a gluten-free diet (GFD) but continue to restrict gluten as they report ‘feeling better’.”

So they set out to discriminate between mental and gastrointestinal symptoms in NCGS by a double-blind cross-over study in which their subjects received one of three dietary challenges for 3 days, followed by a minimum 3-day washout before crossing over to the next diet ( the challenge gluten-free food was supplemented with gluten, whey (16 g/day) or not supplemented = placebo. Depression scores as assessed by the Spielberger State Trait Personality Inventory (STPI) stood out in association with gluten exposure:

“Gluten ingestion was associated with higher overall STPI state depression scores compared to placebobut not whey. No differences were found for other STPI state indices or for any STPI trait measures. No difference in cortisol secretion was identified between challenges. Gastrointestinal symptoms were induced similarly across all dietary challenges.”

Clinical note:In gluten intolerance there is often cross-reactivity to bovine dairy proteins due to similarities in antigen morphology.

The authors conclude:

“Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten-specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptoms.”

Clinical note: Practitioners should bear in mind that FODMAP (Fermentable Oligo-Di-Monosaccharides and Polyols) intolerance can coexist with non-celiac gluten sensitivity wherein the former produces gastrointestinal symptoms while the latter accounts for depression and other neuropsychiatric illness.

Bipolar disorder, like a host of other psychiatric illnesses, should be assessed for neuroinflammation and its underlying causes as evidenced by a wealth of recently published studies. The authors of a paper recently published in the Journal of Neuroinflammation state:

“Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders).”

Regarding the use of antiinflammatory agents in the treatment of psychiatric disorders they state:

“Several human and animal studies suggest that certain antiinflammatory drugs may play an important adjunctive role in the treatment of psychiatric disorders…Although current immune therapies (for example, IVIG, plasmapheresis, corticosteroids and immunosuppressive agents) are often effective for treating autoimmune encephalitides wherein inflammation is acute, intense and predominately of adaptive origin, their efficacy in classical psychiatric disorders wherein inflammation is chronic, much milder, and predominately of innate origin, is limited. Development of novel therapeutics should aim at reversing glial loss, down-regulating harmful MAP [microglial activation and proliferation], while optimizing endogenous neuroprotective T regs and beneficial MAP, rather than indiscriminately suppressing inflammation as occurs with current immunosuppressive agents. Additionally, development of potent co-adjuvant antioxidants that would reverse oxidative injury in psychiatric disorders is needed.”

In reference to bipolar disorder specifically the authors of a paper published in Current Psychiatry Reports state:

“Bipolar disorder is now known to be associated not only with highly prevalent co-occurring psychiatric and substance use disorders but also with medical comorbidities, such as cardiovascular diseases, diabetes mellitus, obesity and thyroid dysfunction. Inflammatory disturbances repeatedly observed in bipolar disorder, can explain some of the comorbidity between bipolar disorder and medical disorder. This revised perspective of bipolar disorders should promote the development of therapeutic tools.”

In particular…

“Immuno-inflammatory dysfunction may well represent a significant component of the underlying pathophysiology of the disorder. We therefore propose to review the immuno-inflammatory hypothesis in bipolar disorder considering the co-occurence with autoimmune diseases, immunological and inflammatory markers, as well as immuno-genetic markers which could lead to personalized treatments.”

A recent paper in the Australian & New Zealand Journal of Psychiatry strikes a similar chord and highlights the role of autoimmunity:

“Increasing evidence suggests that inflammation and immune dysregulation play an important role in the pathogenesis of bipolar disorder. Because the brain can be affected by various autoimmune processes, it is possible that some psychiatric disorders may have an autoimmune basis.”

In review of the literature on peripheral and central immune dysregulation and autoimmunity in bipolar disorder they note, in addition to the mechanisms described above, association with common autoimmune conditions such as SLE and autoimmune thyroiditis:

“Neuroinflammation and peripheral immune dysregulation may play a role in the pathophysiology of bipolar disorder. This involves a complex interaction between immune cells of the central nervous system and periphery resulting in cellular damage through mechanisms involving excitotoxicity, oxidative stress, and mitochondrial dysfunction. Neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are important differentials for a psychiatrist to consider when suspecting autoimmune encephalopathy.”

The authors conclude:

“The link between immune dysregulation, autoimmunity, and bipolar disorder may be closer than previously thought. Psychiatrists should be vigilant for autoimmunity in presentations of bipolar disorder due to its high morbidity and therapeutic implications. Advances in neuroimaging and biomarker identification related to immune dysregulation and neuroinflammation will contribute to our knowledge of the pathophysiology of bipolar disorder.”

In a paper published in the Journal of Affective Disorders, the authors examine the incidence of comorbid medical disorders and present evidence that…

“…bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.”

They dispense with the notion that comorbid medical disorders are entirely due to the deleterious effects of psychotropic medications:

“Until recently, a lot of emphasis has been put on the fact that psychotropic medication contributes to cardiovascular risk factors. Lithium can cause weight gain and adversely influence glucose metabolism, valproic acid is associated to weight gain and insulin resistance, second generation anti-psychotics are associated to hyperlipidemia, increased risk with diabetes, and weight gain though the extent of weight gain depends on which antipsychotic is used. It should however be stressed that the increased mortality rate in bipolar predate modern pharmacologic treatments. In addition, the fact that the association between cardiovascular risk factors and bipolar disorder remains significant after controlling for these co-factors strongly suggests that mechanisms specific to bipolar disorder itself have yet to be identified.”

And in fact inflammation is common to both:

“Inflammation has been shown to be crucial throughout atherosclerosis from endothelial dysfunction to plaque rupture and thrombosis; a number of studies also suggest that inflammation may be implicated in the pathophysiology of bipolar disorder (for review see, Goldstein et al., 2009). The data supporting the hypothesis that inflammation could be a common factor underlying both cardio-vascular and bipolar disorder is important to be reviewed.”

Moreover…

“Over the last two decades, it has been shown that inflammatory processes and neural immune interactions are involved in the pathophysiology of major depression, these data also shed light on how to explain the plausible link between increased levels of cytokines and mood states in bipolar disorder. A pro-inflammatory state is known to activate the tryptophan and serotonin-degrading-enzyme, indoleamine 2–3 dioxygenase (IDO), which has been found elevated in the plasma of bipolar patients. Activation of this enzyme leads to increased consumption of tryptophan, thus reducing the availability of serotonergic neurotransmission, as well as inducing the production of detrimental tryptophan catabolites with neurotoxic effects. It has also been shown that the activity of dopaminergic system is reduced in response to inflammation while cytokines enhance the re-uptake of monoamine neuro-transmitters thereby reducing their intra-synaptic concentrations in the brain.”

“The pro-inflammatory cytokines also induce decrease in neurotrophins, and in particular diminished levels of Brain-Derived-Neurotrophic-Factor (BDNF) leading to decrease neuronal repair, decrease in neurogenesis and an increased activation in glutamatergic pathway which also contributes to neuronal apoptosis. It is noteworthy that serum BDNF has been associated both with changes in mood states in bipolar disorder as well as in coronary heart diseases.”

The autoimmune component is of premiere importance:

“A relationship between auto-immune disorders and bipolar disorder has been reported as early as 1888. Patients with bipolar disorder tend to develop organ-specific autoimmunity as shown, for example, by thyro-peroxidase antibodies (TPO-Abs) associated with thyroid failure, by antibodies to H/KAT-Pase associated with atrophic gastritis and by GAD65A, isoform of glutamic acid decarboxylase which is a marker of type-I diabetes. Recently, manic episodes with psychotic symptoms were observed during acute encephalitis with antibodies directed in particular against extracellular domains of the glutamatergic NMDA receptor. In addition, it has recently been reported that gastrointestinal processing of food antigens such as bovine caseins and wheat glutens is altered in bipolar disorder. Bipolar patients have been reported to have increased antibodies to gliadin, a glycoprotein derived from the ingestion of gluten from wheat or to casein activation, particularly during mania…Presence of these auto-antibodies might even precede the onset of bipolar disorder, as an increased prevalence of Multiple Sclerosis, thyrotoxicosis, ulcerative colitis, psoriasis and rheumatoid arthritis has been reported in unaffected relatives of patients with BD.”

The authors of a paper just published in Current Opinion in Psychiatry note:

“Recent studies have shown that bipolar disorder involves microglial activation and alterations in peripheral cytokines and have pointed to the efficacy of adjunctive anti-inflammatory therapies in bipolar depression.”

They summarize their findings by stating:

“The presence of active microglia and increased proinflammatory cytokines in bipolar disorder suggests an important role of inflammatory components in the pathophysiology of the disease, as well as a possible link between neuroinflammation and peripheral toxicity.”

Inflammatory microglial activation due to a dysregulated immune system is identified as a key factor in psychosis of all types in a paper just published in Biological Psychiatry:

“Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions.”

Microglia are the immune cells of the brain, functioning as macrophages do in peripheral tissues…

“Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model.”

The ‘two-hit’ model features strongly in a multitude of immune and other disorders:

“Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.”

A study also published recently in the Journal of Affective Disorders highlights C-reactive protein (CRP) as an inflammatory marker in bipolar disorder. The authors note:

“Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder.”

They measured CRP in 107 subjects with bipolar disorder correlated with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as a metric for cognitive function and found a significant association:

“There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile and the 75th percentile of the control group. There was an inverse relationship between CRP levels and performance on RBANS total ; RBANS immediate memory; RBANS attention; RBANS language…”

The authors conclude:

“Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.”

CRP also sorts out as a marker of brain inflammation in a study recently published in the journal Neuropsychobiology:

“C-reactive protein (CRP), a marker of underlying low-grade inflammation, has been associated with the pathophysiology of bipolar disorder. Additionally, bipolar disorder may be accompanied by functional or structural cerebral alterations. We attempted to discover whether serum high-sensitivity CRP (hs-CRP) levels are linked to the structural volume change of a specific brain region along with cognitive performance.”

“Elevation of serum hs-CRP levels, an indicator of inflammation, may be associated with reduced volume of the orbitofrontal cortex. Persistent inflammation in the euthymic phase of bipolar disorder may involve the pathogenesis or pathophysiology of alteration of the frontal pathway.”

Cytokines, ‘immune messenger molecules of inflammation’, are naturally also observed in bipolar disorder as documented in a meta-analysis recently published in the Journal of Psychiatric Research:

“Bipolar disorder may be associated with peripheral immune system dysfunction…Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states.”

The authors conducted a meta-analysis of eighteen studies with a total of 761 bipolar disorder patients and 919 healthy controls comparing cytokine concentrations and found…

Of course, pro-inflammatory cytokines have been recognized in the pathophysiology of depression for years as described in a much earlier paper published in the journal Trends in Immunology:

“Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules. In addition, therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been found to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior.”

Regarding the role of stress and the autonomic nervous system in inflammation:

“Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways.”

The two-hit model comes into play in the sense that earlier adaptations may set the stage for a subsequent trigger:

“…depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation.”

The authors of a paper published in Medical Hypotheses describe pro-inflammatory cytokines as a mechanism shared by both bipolar disorder and migraine:

“A bi-directional association between mood disorders and migraine has been consistently reported… we review evidence for the role of inflammatory cytokines in the neurobiology of bipolar disorder and migraine. In addition, inflammation is hypothesized to be a shared pathophysiological mechanism subserving the bipolar disorder and migraine concomitance.”

And it stands to reason that…

“A derivative of this hypothesis is that pharmacological treatments primarily targeting the inflammatory system may have symptom suppressing effects in bipolar disorder.”

Another study published in the Journal of Affective Disorders examines the specific inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in regard to bipolar disorder and response to lithium:

“The role of inflammation in bipolar disorder has recently emerged as a potential pathophysiological mechanism. Tumor necrosis factor-alpha (TNF-α) modulation may represent a pathogenic molecular target and a biomarker for staging bipolar disorder. In this context, the possible association between lithium response and TNF-α level was examined.”

The authors assessed the TNF-α level in 60 bipolar patients receiving lithium therapy in correlation with the ALDA lithium response scale (LRS) to evaluate longitudinal lithium response and found a clear association:

“There was a significant increase in TNF-α level in patients with poor lithium response compared to those with good response, also after controlling for a range of potential confounders.”

Their conclusion is significant both for the role of inflammation marked by TNF-α in bipolar disorder and case management utilizing lithium:

“This study strengthens the hypothesis that TNF-α level may mark or mediate lithium response, and that continuous immune imbalance in poor lithium responders may occasion treatment resistance. Further investigation of immune alterations in treatment-resistant bipolar patients may be productive.”

The key clinical questions are (1) what are the underlying causes of inflammation? and (2) what sound therapies can be applied to those causes? A paper published recently in BMC Medicine discusses several common contributing causes:

“We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’“

“There is also evidence that many other major psychiatric disorders are accompanied by activation of inflammatory and cell-mediated immune pathways, for example, mania, schizophrenia, post-traumatic stress disorder (PTSD)…A recent meta-analysis confirmed that mania and bipolar disorder are accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. Based on the first results obtained in schizophrenia, Smith and Maes in 1995 launched the monocyte-T lymphocyte theory of schizophrenia, which considered that activation of immuno-inflammatory processes may explain the neurodevelopmental pathology related to gestational infections. Results of recent meta-analyses showed that schizophrenia is accompanied by activation of inflammatory and cell mediated pathways. PTSD patients also show higher levels of pro-inflammatory cytokines, including IL-1, IL-6 and TNFα…It is evident that the sources of inflammation and immune activation, which play a role in depression, may contribute to the inflammatory burden in patients with mania. Schizophrenia is also associated with some but not all sources of inflammation and immune activation that play a role in depression. For example, a recent review showed that stress and trauma (first and second hits), nutritional factors and vitamin D may play a role in schizophrenia. The strong associations among schizophrenia and smoking, obesity, some atopic disorders, sleep disorders and poor periodontal and oral health may further contribute to the inflammatory burden in schizophrenia patients.”

Regarding the treatment and prevention of bipolar disorder, depression and other psychiatric illnesses the authors conclude:

“The pivotal element is that most of these are plastic, and amenable to intervention, both therapeutic and preventative…Psychiatry largely lacks an integrated model for conceptualizing modifiable risk factors for depression. It has, therefore, lacked conceptually and pragmatically coherent primary prevention strategies, prioritizing the treatment of established disorders. Yet the rationale, targets and imperative to focus on prevention of depression at a population level is clear.”

Further evidence for maternal infection as a trigger for autoimmune brain inflammation in bipolar disorder is presented in a study hot off the digital presses from the American Journal of Psychiatry:

“The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features.”

Their data disclosed a specific connection with bipolar disorder with psychotic features:

“…maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features…The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.”

Interestingly, in a comment on this study published online in NEJM (New England Journal of Medicine) Journal Watch, psychiatrist Joel Yager, MD states:

“Together with research linking maternal influenza to schizophrenia risk, the current finding that influenza during pregnancy greatly increases the risk for bipolar disorder with psychotic features points to potentially similar prenatal mechanisms in the pathogenesis of diverse psychotic disorders. Other research suggests that prenatal priming of such vulnerabilities is in part due to prenatal immune activation of dopaminergic hyperactivity. Overall, such observations hint at common features and mechanisms in psychosis and may lead to better diagnostic conceptualizations.”

It stands to reason then that anti-inflammatory strategies must figure prominently in case management of bipolar disorder and other psychiatric conditions. The authors of a paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry highlight the use of anti-inflammatory agents:

“Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy…During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders.”

Furthermore, the depredations of brain inflammation encompass a wide range:

“Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces ‘sickness behavior’ resembling depressive symptomatology…Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes.”

They identify several anti-inflammatory agents under investigation:

“Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy…”

Foods, especiallygluten and casein, must never be overlooked as potential triggers of neuroinflammation in bipolar disorder. A study recently published in the journal Bipolar Disorders focuses on this clinically important topic. The authors are also attentive to the issue of gastrointestinal inflammation and compromised barrier function as a sensitizing factor:

“Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.”

They examined GI inflammation using ASCA in 207 non‐psychiatric controls, 226 in patients with bipolar disorder without a recent onset of psychosis, and 38 patients with bipolar disorder with a recent onset of psychosis, comparing it to antibodies against gluten, casein, Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV‐1), influenza A, influenza B, measles, and Toxoplasma gondii and found a marked association with gluten and casein:

“Elevated ASCA conferred a 3.5–4.4‐fold increased odds ratio of disease association that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups, and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group.”

The authors conclude:

“Elevated seropositivity of a GI‐related marker and its association with antibodies to food‐derived proteins and self‐reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder.”

Case management of neuroinflammation and the numerous and complex elements of autoimmunity could hardly be covered in a massive textbook much less a post here. A few among many potential therapeutic agents can be considered here by way of example.

The authors of a paper just published in the journal Neurochemistry International offering interesting evidence that alpha-lipoic acid can protect against neuroinflammation in neuropsychiatric disorders:

“Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial…Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity.”

“Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction.”

They treated glial cultures viral mimetic dsRNA LA reduction of the effects of glial signaling, in other words a dampening of inflammation signaling:

Considering the crucial role of glutathione metabolism and glutamate expression in regulation of neuroimmunity, their findings in this regard are of particular interest:

“In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cystine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA.

Clinicians should consider the authors’ conclusion:

“This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders.”

Cucurmin, of course, is always worthy of consideration in case management of inflammatory and autoimmune disorders. The authors of a paper published last spring in Medical Hypotheses comment on the use of curcumin for bipolar disorder:

“Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa)…Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.”

Interestingly, aspirin is a potential therapeutic agent for bipolar disorder and other mental illnesses. An excellent paper recently published in BMC Medicine extensively reviews the mechanisms for its beneficial effects. Regarding the position of aspirin and other anti-inflammatory agents in the evolution of therapy for neuropsychiatric disorders:

“Historically, treatment options for common neuropsychiatric disorders, including depression, schizophrenia, and bipolar disorder, have focused on medications that modify the activity of monoamine neurotransmitter systems. Monoamines may play a large role in the pathophysiology of these disorders, but the monoaminergic theory of illness has failed to deliver novel agents beyond the limited treatment options currently available. There is now a clear body of recent evidence to support an etiologic role for other factors in the pathophysiology of depression, schizophrenia, and bipolar disorder, including oxidative and nitrosative stress (O&NS), mitochondrial dysfunction, and activation of the immune-inflammatory system.”

Specifically for aspirin:

“There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer’s disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory ‘braking signals’, including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)-6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.”

Regarding the autoimmune aspect:

“To further support a role for therapeutic agents targeting inflammation in psychiatry, there is a large body of evidence linking autoimmune disease to psychiatric disorders. For example, clinical depression is associated with diverse autoimmune disorders, including diabetes type 1 and 2, inflammatory bowel disease, psoriasis, rheumatoid arthritis, atherosclerosis, lupus erythematosus, and multiple sclerosis (MS). Patients with clinical depression have a high degree of auto-immunity directed against a number of different selfepitopes, including serotonin and phospholipids (for example, cardiolipin and antinuclear factor). Recently, a new type of autoimmune response has been described, which is an autoimmune response secondary to O&NS damage [oxidative and nitrosative damage]. Thus, it is possible that increased O&NS levels may damage endogenous molecules, such as fatty acids and proteins, thereby changing their structure. As a consequence, the O&NS-modified self determinants may be rendered immunogenic, and an autoimmune response is then directed against the modified epitopes (neo-epitopes). For example, clinical depression is accompanied by IgG-mediated immune responses directed against oxidized low-density lipoprotein. Moreover, there is an association between this kind of autoimmune response and progression (or staging) of depression. Consequently, some of these autoimmune responses are significantly higher in depressed individuals with chronic depression (duration of >2 years) compared with patients who are depressed but do not have chronic depression. These findings suggest that O&NS damage, the consequent formation of neo-epitopes, an enhancement of the natural autoimmune response, and even a transition to pathological damaging auto-immunity increase the risk of neuroprogression and of chronic depression.”

The authors also note the interplay between genetic potential and the expression of autoimmunity in bipolar disorder:

“Evidence from the literature on bipolar disorder also supports the role of a genetic component; patients with bipolar disorder and their relatives have been shown to be more prone to develop thyroid auto-immunity, and this association is not attributable to the use of lithium or to the severity of psychiatric symptoms. Moreover, in addition to a higher prevalence of thyroid autoantibodies, patients with bipolar disorder have a higher prevalence of organ-specific autoantibodies, including autoantibodies to hydrogen/potassium ATP and glutamic acid decarboxylase-65. The aforementioned Danish national study confirmed these findings by showing an association of bipolar disorder with a family history of pernicious anemia, and with presence of Guillain-Barré syndrome, inflammatory bowel disease, and autoimmune hepatitis in individual patients.”

As for indicating the use of aspirin:

“Collectively, these findings imply shared immune pathogenic factors for mood disorders, schizophrenia, and organ-specific autoimmune diseases. One of these shared factors is thought to be an intrinsically high activation set-point for the MPS [mononuclear phagocyte system, in this case monocytes present as microglia in the brain]. It is thought that the high activation set-point of these cells of the MPS can be down-regulated by aspirin.”

While on the topic of aspirin, it’s worth noting a study published last summer in Bipolar Disorders offering evidence that aspirin improves lithium-related sexual in men with bipolar disorder:

“The aim of the present study was to assess the effect of aspirin on lithium‐related sexual dysfunction in men with stable bipolar affective disorder (BAD).”

The authors staged a randomized, double‐blind, placebo‐controlled study, in which 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. They used the International Index for Erectile Function (IIEF) was used to assess sexual symptoms at the start, week 3, and week 6. The results were gratifying:

“Significant effects of time × treatment interaction were observed for total score [Greenhouse–Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse–Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total(63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups.”

Bottom line: There is a massive amount of evidence supporting the importance of assessing and treating neuroinflammation in bipolar disorder and other neuropsychiatric illnesses. This makes necessarily the comprehensive examination of autoimmunity and its numerous underlying contributory causes. Past and future posts focus on this crucial dimension of clinical practice.

Multiple sclerosis (MS) becomes evident as the silent creeping damage of the immune system’s destruction of myelin crosses the threshold of sensibility. Additional evidence that loss of tolerance to gluten can be a contributing cause in multiple sclerosis is offered in a study published in Acta Neurologica Scandinavica. This deserves reflection because many clinicians seem to disregard that non-celiac gluten sensitivity may present with no other symptoms. The authors state:

“Multiple changes in antibodies against various antigens are found in multiple sclerosis (MS)… We wanted to measure immunoglobulin A (IgA) antibodies to some common food antigens in MS and also IgG against gliadin and gluten.”

They measured serum IgA antibodies were measured against gluten, gliadin, lactoglobulin, lactalbumin, casein and ovalbumin in patients with multiple sclerosis and unafflicted controls. They added measurements of IgG for gluten and gliadin. The data showed a very strong correlation in multiple sclerosis with the antibodies for gluten and milk:

“Highly significant increases compared with controls were found for IgA and IgG antibodies against gliadin and gluten. IgA antibodies against casein were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative.”

Clinical note: The absence of anti-transglutaminase antibodies means of course that these are non-celiac cases, rather the reaction to gluten was fueling multiple sclerosis.

The authors’ conclusion brings to the mind the issue of compromised intestinal barrier function (‘intestinal permeability’):

“The data presented indicate that there may be a possible moderately increased uptake of some specific proteins from the gut in MS compared with controls.”

Hyperexcitable brain, with potentially severe consequences, is recognized as among the gluten-related autoiimmune neurological disorders in a paper just published in the Journal of Neurology, Neurosurgery & Psychiatry. The authors state:

“Hyperexcitable brain and refractory coeliac disease: a new syndrome Gluten related disorders (GRD) is the newly proposed term to encompass a spectrum of immune mediated diseases triggered by gluten ingestion. Whilst coeliac disease (gluten sensitive enteropathy) remains one of the best characterised GRD, neurological dysfunction is one of the commonest extraintestinal manifestations with a range of presentations such as cerebellar ataxia, neuropathy, sensory ganglionopathy and encephalopathy (headaches and white matter abnormalities). Neurological manifestations can occur with or without enteropathy.”

They documented the clinical and electrophysiological characteristics of this hyperexcitable brain syndrome in a severely afflicted group of seven patients:

“The 7 patients (5 male, 2 female) were identified from a cohort of 540 patients with neurological manifestations of GRD that regularly attend our gluten/neurology clinic. The mean age at onset of the neurological symptoms was 58 years (range 46 to 76). Unlike myoclonic ataxia (eg in the context of opsoclonus myoclonus ataxia syndrome) the myoclonic tremor in these patients was initially focal (face, tongue one arm and/or one leg) but then spread to affect other parts of the body. Epilepsy was a feature in 5 of the patients, 3 of which gave a history of Jacksonian march before progression to generalised seizures. In one patient the neurological presentation was with status epilepticus. All patients had a mild degree of limb ataxia and more prominent gait ataxia. Electrophysiology showed evidence of cortical myoclonus. Four had a phenotype of epilepsia partialis continua and three later developed more widespread jerking. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases but this was not the main source of disability by contrast to patients with gluten ataxia, where cerebellar ataxia is the most disabling feature.”

Neuroinflammation due to celiac and non-celiac gluten sensitivity can cause a range of neurological disorders. These cases are notable for their severity and association with refractory celiac disease (CD that fails to heal after gluten is eliminated). They are especially troubling because the damage and hyperexcitable brain symptoms remained after gluten was eliminated:

“All patients adhered to a strict gluten–free diet with elimination of gluten–related antibodies, despite which there was still evidence of enteropathy in keeping with refractory celiac disease (type 1 in 5 and type 2 in 2). One of the 2 patients with type 2 refractory enteropathy died 13 years later from metastatic enteropathy–associated lymphoma. The other died 1 year after the neurological presentation from presumed enteropathy associated lymphoma. Four were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Whilst their ataxia improved the myoclonus remained the most disabling feature of their illness with a tendency to spread and affect other parts of the body.”

Clinical note: Practitioners should not underestimate the potential severity of gluten-associated neuroinflammation. We should be alert to the far more common milder manifestations of hyperexcitable brain that can present as sleep disorders, anxiety, attention disorders, sympathetic nervous system hyperarousal syndromes, etc. The authors conclude:

“This syndrome whilst rare, appears to be the commonest neurological manifestation of refractory CD. The clinical manifestations extend from focal reflex jerks to epilepsia partialis continua, covering the whole clinical spectrum of cortical myoclonus. This entity is possibly under–diagnosed and difficult to treat.”

Neuropsychiatric illness often involves brain inflammation for which there may be an autoimmune origin. The authors of a paper* recently published in Current Opinion in Rheumatology set out to…

“…illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets.”

They describe the science emerging on underlying mechanisms behind the observations that both exposure to infectious agents and autoantibodies without evidence of pathogens can cause brain disorders…

“…….evidence accumulates to support the idea that dysregulated cross-talk between the brain and the immune system is an important contributor to the pathogenesis of conditions as diverse as schizophrenia, mood disorders, autism spectrum disorders (ASDs), obsessive-compulsive disorder (OCD), Tourette syndrome and other tic disorders, attention-deficit hyperactivity disorder (ADHD), anorexia nervosa, narcolepsy, posttraumatic stress disorder and myalgic encephalomyelitis/chronic fatigue syndrome (CFS). In addition, intriguing new evidence lends support to the possibility that not only the microbes associated with infectious episodes but also the bacteria of the gut microbiome can foster the production of brain-reactive autoantibodies, and that these microbe-induced antibodies provide the critical link between infection and neuropsychiatric disorders.”

In the case of infection, it may not even matter so much what the infectious agent is…

“A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development.”

Noting that shifts in maternal immune activation toward an autoimmune and allergic phenotype predisposed offspring to autism-like behaviors which were subsequently abolished by bone marrow transplantation to modify immune expression…

“In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects.”

While breaching of the blood brain barrier (BBB) immunoreactive agents into the privileged space of the central nervous system, it may not always be necessary for the manifestation of neuropsychiatric symptoms:

“Another study that focused on GAS [group A streptococcus]-related, CNS-directed autoimmunity raised the intriguing suggestion that alternate transport systems may exist for entry of certain immunoglobulin isotypes or subclasses into the CNS. Zhang et al. injected naïve mice with anti-GAS IgM monoclonal antibodies, without the use of an adjuvant to breach the BBB, and found increased stereotypic behaviors…Transcellular mechanisms that obviated the need to compromise BBB integrity were postulated to facilitate the entry of these IgM antibodies into the CNS.”

Pathogens aren’t the only microbes that can incite autoimmune activity. As noted in earlier posts, the ‘normal’ commensal microbiota can also participate in loss of immune tolerance:

“Recent evidence suggests that both pathogenic and commensal microbes play a role in the pathogenesis of a subset of neuropsychiatric disorders through induction of brain-reactive autoantibodies. Whereas infection with certain pathogens can trigger autoantibody production through molecular mimicry, commensal bacteria that comprise the gastrointestinal microbiota probably set the stage for the development of autoimmune responses by skewing immune responses toward overproduction of Th17 cells and reduction in numbers and function of Tregs.”

The authors also note the role of antioxidants and depletion of the antoxidant system, particularly glutathione:

“Failed uptake of antioxidant precursors in the terminal ileum, influenced by differences in tryptophan degradation capacity of the microbiota and related factors, may also contribute to a skew toward autoimmunity by reducing levels of Tregs and increasing levels of autoimmunity-provoking Th17 cells.”

The link between schizophrenia and Toxoplasma gondii infection is illustrative:

“There is also evidence that the microbial infection itself is not likely to be as important in pathogenesis as the presence of antibodies to the microbe, as well as the isotype and binding characteristics (cross-reactivity, affinity and avidity) of these antibodies. Anti-toxoplasma antibodies may also be more prevalent in individuals with bipolar disorder, type 1.”

Moreover…

“In individuals with schizophrenia, antibodies directed against food antigens, including bovine milk casein and wheat-derived gluten, are correlated with the presence of antibodies to T. gondii…In a separate study, increased levels of anti-gliadin antibodies were found in individuals with schizophrenia. Furthermore, the interactomes of nine neuropsychiatric disorders, including multiple sclerosis, Alzheimer’s disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson’s disease, ADHD and ASD, but not anorexia nervosa or myalgic encephalomyelitis/CFS, showed significant overlap with the interactome of T. gondii, and has been closely associated with a number of autoimmune diseases.”

Interestingly, autoimmunity with loss of tolerance to gluten may involve reduced antioxidant capacity:

“The relationship of anti-toxoplasma antibodies to anti-gliadin antibodies in some neuropsychiatric disorders may relate to reduced antioxidant capacity in the terminal ileum. Gliadin, a major protein component of wheat that is associated with celiac disease, also appears able to dysregulate redox balance in peripheral blood mononuclear cells, triggering allergic-type responses that include specific enhancement of IL-4-mediated IgE production…A clearer understanding of these processes may uncover unique strategies for intervention with less potential for toxicity, including antioxidants, prebiotics, probiotics and transplantation of fecal microbiota.”

Clinical note: Clearly practitioners must be alert to the role of autoimmunity in neuropsychiatric disorders and must discriminate between infection and loss of immune tolerance triggered by infection. It may not be so apparent that the indigenous commensal microbiota can play a role in autoimmunity, antimicrobial therapy may modify symptoms for a time but ‘dig the hole deeper’, and that caution must be observed in contemplating treatment for infections that expose the immune system to the lipopolysaccharides of disintegrating bacterial and fungal cells in the presence of active or latent loss of immune tolerance.

The authors conclude:

“Genetically susceptible individuals may generate brain-reactive autoantibodies when exposed to certain infectious agents or commensal organisms. Under inflammatory conditions that promote BBB disruption and facilitate trafficking into the CNS, binding of autoantibodies to cross-reactive epitopes may contribute to the cognitive and behavioral disturbances associated with these disorders by altering brain activity within key circuitry. This conceptual model views altered brain–immune signaling as a product of the interaction of immune response genes and microbial exposures at key points during prenatal and postnatal development, and provides a framework within which discordant findings across studies of different neuropsychiatric disorders may be better explained and through which novel pathways for improved therapeutics may be discovered.”

When your patient’s immune tolerance has improved and it’s time to answer the question “have they re-gained tolerance to selected foods to which they were sensitive?”, a fascinating study published in GUT, An International Journal of Gastroenterology and Hepatology (BMJ Group) offers evidence for the best way to stage a re-test of food sensitivity. The authors’ specific intent was to investigate the dynamics of the response to a gluten challenge in patients with celiac disease who had been on a gluten-free diet:

“Coeliac disease is defined by gluten responsiveness, yet there are few data on gluten challenge (GC) in adults on a gluten-free diet. Lack of data regarding the kinetics of responses to gluten is a limitation in clinical practice and research when GC is performed.”

They fed 20 adults with biopsy-proven celiac disease a gluten dose of 3 or 7.5 g per day for 14 days (yikes), followed by data collection on days 3, 7, 14 and 28 after starting the gluten challenge. They performed duodenal biopsies before the challenge and at days 3 and 14, measuring the villous height to crypt depth ratio (Vh:Cd) and the intraepithelial lymphocyte (IEL) count/100 enterocytes ratio. Importantly for the purpose of re-testing food sensitivity in general they assessed antibodies to tissue transglutaminase and deamidated gliadin peptides. They also included the lactulose to mannitol ratio (LAMA) and symptoms at each visit. Their very interesting data offer helpful parameters:

“Significant reduction in Vh:Cd (2.2–1.1, p<0.001) and increase in IELs (32.6–51.8, p<0.001) were seen from baseline to day 14. Antibody titres increased slightly from baseline to day 14 of GC but markedly by day 28. LAMA did not change significantly. Gastrointestinal symptoms increased significantly by day 3 and returned to baseline by day 28. No differences were seen between the two gluten doses.”

There are valuable points to be taken. The most important for the purpose of food sensitivity re-testing is the trajectory of antibodies following the allergen (gluten) challenge: A marked increase in the antibodies tested was not observed until the 28 day measurement. This means that re-testing much earlier than 25-30 days after a challenge significantly increases the risk of false negatives.

Additionally, I have not found the lactulose-mannitol ratio to be an accurate indicator of loss of gut barrier integrity (intestinal permeability), and these investigators saw no significant change throughout their trial. I much prefer the Intestinal Antigenic Permeability Screen offered by Cyrex Laboratories. These authors conclude:

“14 day GC at ≥3 g of gluten/day induces histological and serological changes in the majority of adults with coeliac disease. These data permit accurate design of clinical trials and indicate that many individuals will meet coeliac diagnostic criteria after a 2-week GC.”

Clinical note: though we have to ask to what degree a gluten challenge study applies to other food sensitivities this does suggest a way to go forward. Unless future evidence indicates otherwise, I believe that I am minimizing the risk of misleading false negatives in food sensitivity re-testing by having my patients consume the foods in question for a week, then waiting until days 25-30 to have their blood drawn.

One other point specific to gluten: the antibodies peaked at day 28, they did not subside then. Others have documented the persistence of gluten antibodies until 240 days after gluten avoidance is initiated, and the subsidence of GI symptoms does not insure that important non-celiac inflammatory effects are resolved within a month.